The research proposed in this SCOR application is aimed at the basic mechanisms, epidemiology, diagnosis and clinical consequences of sleep-disordered breathing (SDB). In healthy human subjects and in chronically instrumented unanesthetized animals, we will address three fundamental physiologic effects of sleep: a) the site and mechanism of action of hypocapnic-induced apnea; b) the contributions of fluctuating sleep state to breathing stability and upper airway dimensions; and c) the effects of sleep-induced changes in upper airway resistance on respiratory muscle recruitment. Four types of more narrowly focused longitudinal, clinically-oriented experiments address important issues related to SDB: a) humoral mechanisms of hypertension in the patient with SDB; b) cell biology of nocturnally-induced asthma; c) the effects of obesity and its reversal on the magnitude and site of sleep- induced airway obstruction; and d) application of the concept of the sleep-induced apneic threshold to patients with neuromuscular weakness and chronic lung disease as a means of intermittently "resting" respiratory muscles. Finally, our single largest undertaking brings an epidemiologic focus to the problem of cardiopulmonary disorders of sleep, predicated on the absolute necessity for longitudinal studies of a population-based sample in order to determine the natural history of these disorders. Our nested longitudinal study design, based on careful considerations of statistical power and advanced methods, will result in an ongoing elucidation of the natural history, risk factors and consequences of sleep disordered breathing. Critical to this study is the need for a comprehensive, sensitive, valid, quantitative test of the essential features of sleep disordered breathing, which is applicable to large numbers of subjects. We will design and validate such a test and use this broad and rigorously defined data base to determine the predictors of sleep disordered breathing and its clinical consequences in our population-based studies.